In vitro fertilization (IVF) is a method for establishing pregnancy in a female subject. The procedure typically involves ovarian stimulation with one or various hormones, mainly follicle-stimulating hormone (FSH), and human chorionic gonadotropin (hCG) is usually administered to trigger final follicular maturation. Oocyte retrieval takes place generally 2 days (around 36 h) after hCG administration. The ooctyes are then fertilized in vitro, cultured for several days, and are transferred into the uterus. IVF also encompasses the transfer of embryos originating from the eggs of a first female (the donor) into a second female (the gestational carrier). Embryos may be placed in frozen storage and transferred (i.e., frozen embryo transfer) after several months or even years.
Improving the implantation rate of transferred embryos is one of the major challenges in assisted reproductive technologies (ART) treatment. Approximately only one-third of the transferred embryos implant in women undergoing controlled ovarian stimulation for IVF/intracytoplasmic sperm injection (ICSI). Implantation and pregnancy rates are influenced by multiple factors related to the age and other characteristics of the patient, the magnitude of the response to ovarian stimulation, the quality of the embryos obtained, the endometrial receptivity as well as the actual transfer procedure.
Uterine contractility is considered a potentially important factor affecting implantation and pregnancy rates in IVF/ICSI cycles (Fanchin et al. 1998; Schoolcraft et al. 2001; Bulleti and de Ziegler 2005). A high frequency of uterine contractions at the time of transfer appears to have a negative impact on outcome, possibly by expelling the embryos in the uterine cavity or by displacing the embryos and thereby reducing implantation and pregnancy rates.
Observational data indicated a decrease in clinical pregnancy rates with increasing frequency of contractions at the time of cleavage-stage embryo transfer at hCG+4 days (i.e., four days after hCG administration, corresponding to day 2 post-retrieval of oocytes) (Fanchin et al. 1998). A prospective controlled study also observed that patients with a higher frequency of uterine contractions on the day of cleavage-stage embryo transfer (day 3 post-retrieval) had lower pregnancy rates than patients with lower frequency of uterine contractions at the time of transfer (Zhu et al. 2014).
Uterine contractility in controlled ovarian stimulation cycles has been compared to normal menstrual cycles (Ayoubi et al. 2003). The frequency of uterine contractions was found to be similar between the timepoint of hCG administration in a controlled ovarian stimulation cycle and at the time of luteinizing hormone (LH) surge in a natural cycle. In the luteal phase, the frequency of uterine contractions was higher at hCG+4 days (corresponding to day 2 post-retrieval) in a controlled ovarian stimulation cycle compared to at LH+4 days (i.e., four days after LH surge) in a natural cycle (Ayoubi et al. 2003). However, the frequency of uterine contractions at LH+6 days and hCG+6 days (corresponding to day 4 post-retrieval) was not different and in both situations was low, indicating identical level of uterine quiescence at that time point in controlled ovarian stimulation and natural cycles (Ayoubi et al. 2003). In another study, uterine contractility was assessed at the day of hCG administration, hCG+4 days (corresponding to day 2 post-retrieval) and hCG+7 days (corresponding to day 5 post-retrieval) in women undergoing a controlled ovarian stimulation cycle (Fanchin et al. 2001). The frequency of uterine contractions was highest at the day of hCG administration, decreased slightly during the early luteal phase as assessed at hCG+4 days, and reached nearly quiescent status at hCG+7 days (corresponding to day 5 post-retrieval). Another study reported a decrease in the number of junctional zone contractions in oocyte donors in the early luteal phase from day 2 to day 3 and also to day 4 post-retrieval (Lesny et al. 1999). Similarly, evaluation of uterine contractility in oocyte donors who had undergone controlled ovarian stimulation and received exogenous progesterone luteal phase supplementation indicated that there was a significant decrease in the frequency of uterine contractions from day 2 post-retrieval to day 5 post-retrieval (Blockeel et al. 2009).
The highest level of uterine contractility is at the end of controlled ovarian stimulation (day of hCG administration) and has been attributed to the high serum estradiol and low serum progesterone concentrations at that time point. The decrease in uterine contractility during the luteal phase is believed to be the result of the exposure to endogenous progesterone caused by the corpus luteum function in response to the hCG administration as well as exogenous progesterone luteal supplementation used in IVF/ICSI cycles. Although progesterone supplementation is used for luteal phase support in IVF/ICSI patients and can reduce uterine contractility, there is elevated uterine activity during the early luteal phase (day 2 or 3 post-retrieval) when transfer of cleavage-stage embryos is performed.
As uterine contractility is elevated during the early luteal phase (day 2 or 3 post-retrieval) when transfer of cleavage-stage embryos is performed, investigations assessing the impact of different interventions on uterine contractility for improving implantation have been conducted in the early luteal phase (day 2 and 3 post-retrieval transfer; hCG+4 days). Randomized controlled trials (Moon et al. 2004; Bernabeu et al 2006; Kim et al. 2008; Ng et al. 2014), quasi-randomized controlled trials (Moraloglu et al. 2010), retrospective studies in fresh and frozen embryo replacement cycles (Chou et al. 2011; Lan et al. 2012), or case studies in fresh and frozen embryo replacement cycles (Pierzynski et al. 2007; Liang et al 2009) reporting findings with compounds reducing uterine contractility, like atosiban (Kim et al 2008; Moraloglu et al. 2010; Ng et al. 2014), indomethacin (Bernabeu et al. 2006) and piroxicam (Moon et al. 2004) have been all conducted on day 2 or 3 post-retrieval, i.e., at the time of cleavage-stage embryo transfer.
A recent randomized controlled trial (Ng et al. 2014) compared the treatment outcome after administration of atosiban or placebo in IVF/ICSI patients followed by cleavage-stage embryo transfer on day 2 or day 3 post-retrieval. This large study was designed to determine whether the anecdotal evidence found in the previous smaller studies could be confirmed. This adequately-designed, large (N=800), double-blind, randomized, controlled trial found no significant increase in implantation or live birth rates with atosiban compared to placebo, as illustrated by live birth rates of 39.8% versus 38.0%, respectively (Ng et al. 2014). Atosiban administration on day 2 or day 3 post-retrieval therefore does not significantly increase implantation or live birth rates.
Consequently, improving implantation of transferred embryos remains one of the major challenges in assisted reproductive technologies (ART) treatment. It is an object of the present disclosure to improve implantation rates, thereby increasing pregnancy rates and live birth rates.